ss

1. MedChemComm
REVIEW
Cite this: DOI: 10.1039/c5md00394f
Received 8th September 2015,
Accepted 28th October 2015
DOI: 10.1039/c5md00394f
www.rsc.org/medchemcomm
Endless resistance. Endless antibiotics?
Jed F. Fisher and Shahriar Mobashery
The practice of medicine was profoundly transformed by the introduction of the antibiotics (compounds
isolated from Nature) and the antibacterials (compounds prepared by synthesis) for the control of bacterial
infection. As a result of the extraordinary success of these compounds over decades of time, a timeless
biological activity for these compounds has been presumed. This presumption is no longer. The inexorable
acquisition of resistance mechanisms by bacteria is retransforming medical practice. Credible answers to
this dilemma are far better recognized than they are being implemented. In this perspective we examine
(and in key respects, reiterate) the chemical and biological strategies being used to address the challenge
of bacterial resistance.
Introduction
Franklin's choice of the inevitability of “death and taxes” was
surely not meant as an exclusive list. The modern observer of
the diminishing efficacy of the chemotherapeutic armamen-
tarium against bacterial infection would not hesitate to add
“resistance” to his list. Bacterial resistance was, is, and forever
shall be.1–4
It is found in the hospital, in the microbiome;5
in
the animal manure of farms;6,7
in the soil;8–12
in remote
caves;13
in the permafrost;14,15
in a centuries-old mummy;16
and in the remote reaches of the oceans.17
Moreover, given
the impossibility of removing antibiotics from the environ-
ment—that is, removal of the evolutionary pressure—the evo-
lution of the resistome cannot be reversed.18
We are com-
pelled to live with the evolutionary legacy of antibiotics, both
as ultimate pollutants in the environment and as persistent
genes throughout the microbiome,19
even as we confront the
consequences of this legacy. The question is less what we are
to do, but how this confrontation must be done. The multi-
factorial answers to this question are well known, and have
been expressed in a chorus of different voices.20–38
Some of
the answers to the question of what to do—such as limiting
antibiotics in food sources; improving scientific,39
environ-
mental,40
and clinical stewardship;41–46
and revising clinical
trial design and creating post-registration financial incentives
to reward the commercial investment in antibacterial discov-
ery and development)47,48
—transcend science. The impor-
tance and the inseparability of each of these aspects are well
recognized. Nonetheless, the slow translation of many of
these aspects into the societal and political spheres raises the
question whether the full value of the chemical arsenal
against bacterial infection—the (isolated from Nature)
antibiotics, the semi-synthetic antibiotics, and the synthetic
antibacterials—can be preserved. Until this translation
occurs, how can society, and how can science, sustain the
future of all—both old and new—antibacterial entities? The
immediate task for society is the impeccable husbandry of
the antibacterials that we already possess, as cogently argued
by The Center for Disease Dynamics, Economics, and Policy.49
Nonetheless, their world-wide assessment shows that we
remain well short of this standard. The task for science is to
contribute to the technologies that will contribute to this
stewardship, while simultaneously preparing for the possibil-
ity that stewardship will not be enough. The antibacterial
future will include the pragmatic resurrection (or
repurposing) of existing structures,20,50
identifying advanta-
geous structural permutations of these same structures, and
the discovery of new antibacterial strategies and structures.
The chemistry, biochemistry, microbiology, and medical
aspects of resistance are inseparable. In this brief perspective
we exemplify, using for the most part recent discoveries, how
scientists are confronting resistance in order to secure an
antibiotic future as endless as that of resistance. These dis-
coveries are discussed first from a chemical, and then a bio-
logical, perspective.
Endless antibiotics: a chemical perspective
The most fundamental chemical perspective is the anti-
bacterial as a composition of matter. The simplest proposal
to address the diminishing ability of existing antibacterials is
the discovery of better ones. If only this discovery was the
simple matter of wishing! The daunting challenge of the dis-
covery of new chemical matter that is efficacious, as a result
of the compromise of one of the limited number of validated
bacterial targets, is the theme of two separate lamentations
from two separate industrial discovery teams.51,52
Is anti-
bacterial discovery so exceptionally challenging? The chemical
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Department of Chemistry and Biochemistry, University of Notre Dame, Notre
Dame, IN 46556-5670, USA. E-mail: jfisher1@nd.edu, mobashery@nd.edu
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structures useful against bacterial infection are sourced from
two realms. The first realm is the synthetic: structures that
are unprecedented, or are only partly precedented, in Nature.
The fluoroquinolones are an important example of exception-
ally useful antibacterials having (for the most part) origins in
the synthetic realm.53,54
The second realm is the antibiotics
discovered by Nature, as exemplified by the incredible array
of natural products found during the “golden age” of antibi-
otic isolation and thereafter.55
The interface between the two
realms comprises the structures synthetically elaborated from
the antibiotics of Nature. This transformation is robustly
exemplified by the structure–activity development of the sub-
classes (including the penicillins, cephalosporins, carbap-
enems, monobactams, monocarbams, and monosulfactams)
Scheme 1 Structure–activity development within the “golden age” classes of the antibiotics continues, and certainly will address the future need
for new antibacterials. This Scheme displays structures (identified by their generic name and/or their registry number) that exemplify (but by no
means define) the research frontiers for these classes. The Aminoglycoside class (Column 1) is represented by the late-stage clinical candidate
plazomicin,57
having broad-spectrum activity, low toxicity, and good evasion of the aminoglycoside-modifying enzymes of resistance.58,59
Struc-
ture [1626394-79-3] is an exploratory monosulfonamide-modified derivative of sisomicin with excellent Gram-negative activity and (in mice)
exceptionally reduced ototoxicity.60
Structure [1620221-11-5], a second exploratory aminoglycoside, combines selective deletion of alcohol func-
tional groups (to avoid resistance enzyme modification) with a fluoro-dependent reduction of the basicity of the neighboring amine with a conse-
quent reduction in toxicity.61
Among the recent developments in the β-Lactam antibiotics (Column 2) is the reevaluation of older β-lactam struc-
tures such as temocillin62
and aztreonam. These latter two structures were perceived at time of their entry into the clinic as undesirably
narrow-spectrum. With the proliferation of β-lactamase resistance enzymes over the past two decades, the ability of these older structures to
resist hydrolysis by many β-lactamases is now regarded as advantageous. The antibacterial spectrum of aztreonam is further improved upon
combination with β-lactamase inhibitors.63
The new β-Lactamase Inhibitor class (Column 2) includes the diazabicyclooctane avibactam.64,65
Other members of the diazabicyclooctane class under active investigation include the MK-7615 structure66
and the OP-0595 structure.67
A sec-
ond new exploratory β-lactamase inhibitor, the cyclic boronic acid RPX-7009, restores carbapenem activity to bacteria expressing the KPC
β-lactamase.68
Macrolides within the new Ketolide class (Column 3) are represented by telithromycin and by the newer fluoro-substituted
solithromycin.69
The characterization of the rRNA methylase that confers ketolide resistance to the producing Streptomyces strains will facilitate
the structure–activity development of this class, given the probable eventual transition of this activity as a resistance mechanism.70
New struc-
tures within the Tetracycline class (Column 4) include the clinically-approved tigecyline69
and the exploratory structure omadacycline. Although
the structural difference between the two is subtle, the latter has oral activity.71
A second exploratory class of new tetracyclines is the
hexacyclines.72
Resurgent interest in bacterial Gyrase/Topoisomerase Inhibitors (Column 4) is driven both by the proven clinical value of the
fluoroquinolones and the consequent resistance development.73
A comparison of the structures of moxifloxacin, a recent generation fluoro-
quinolone, with that of the new exploratory structure ETX-0914 (having both Gram-positive and Gram-negative activity) shows superficial simi-
larity (both have a modified fluoroquinoline core). Notwithstanding this similarity and the shared target, the mechanistic difference between the
two is distinct.74,75
ETX-0914 is a clinical candidate targeting Neisseria gonorrhoeae. It is discussed in this review as an outstanding example of
the possible value that synthetic chemical libraries may have for the discovery of new antibacterials.
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of the β-lactam antibacterials.56
The challenge with respect to
the chemistry of antibiotic discovery thus coincides with two
inquiries. Is there opportunity for structural development
within the “golden age” antibiotic structures? Are there
unrecognized compounds with antibacterial activity in the
synthetic structures found in chemical libraries, or to be
found in Nature?
The answer to both questions is “yes”, notwithstanding
the daunting difficulty of realizing chemical answers.51,52
A
sense of the answer to the first question is given by Scheme 1,
where recent structures represent some of the key structural
and mechanistic frontiers for the grand classes of the anti-
bacterials of the golden age of discovery (the amino-
glycosides, the β-lactams, the tetracyclines, the macrolides,
and the quinolones). The focus of the remainder of this
review is the answer to the second question: finding new
antibacterials from chemical libraries and from Nature.
Part of the reason for the perception of a scarceness of
antibacterial matter in chemical libraries is the poor align-
ment between the desirable chemical properties of drugs that
address bacterial, compared to eukaryotic, targets, in such
libraries.76–78
Recognition of this difference has led to the
design of chemical libraries that are biased toward the gener-
ally more polar character of known antibacterials. These
efforts have attained promising results.79
Aligning yet further
the libraries to coincide with the different antibacterial sub-
classes (such as attention to the requirements for optimal
inhibition of cell wall targets compared to the ribosome as a
target) may improve success.80
Nonetheless—and notwith-
standing the reality that successful antibacterial discovery
requires more than optimization of the physicochemical
properties of the chemical library81
—there are antibacterials
waiting to be found in chemical libraries. For example, the
interplay of library screening, synthesis, and the use of
reverse genomics identified the spiropyrimidinetrione inhibi-
tors of the bacterial topoisomerases.82,83
Subsequent struc-
ture–activity effort yielded a lead structure (EXT-0914) with
excellent in vitro activity, and promising in vivo activity,84
against inter alia Neisseria gonorrhoeae.85–87
Likewise, library
screening has had exceptional success in identifying potential
antibacterials targeting Mycobacterium tuberculosis, as evidenced
by both the imidazopyrimidine88–95
and benzothiazinone96–103
classes. As with any such structure, whether natural or syn-
thetic, it remains to be seen whether it has the robustness
(most emphatically, with respect to resistance development)
needed to progress. But the structures are there. The new Com-
munity for Open Antimicrobial Drug Discovery effort is an
opportunity to identify these structures.104,105
This objective of
this effort is to expand the chemical diversity of antibacterial
(and antifungal) compositions of matter through a free screen-
ing program (http://www.co-add.org), requiring submission of
only 1 mg of a pure, water- or DMSO-soluble compound for the
purpose of screening. The results of the screening are “free”
(ownership is retained by the submitters).
Virtual chemical libraries in principle should not have the
limitation of (for example) mismatched physical properties,
but in fact virtual screening shares this same encumbrance
since every virtual structure must have a physical counter-
part. The treatment of disease (alas) will never be virtual.
Nonetheless, the dramatically improved structural under-
standing of validated bacterial targets has provided examples
of successful virtual screening.106
A recent example of suc-
cessful virtual screening include the identification of inhibi-
tors of the Penicillin-Binding Proteins having promising
in vitro Gram-positive activity.107–109
Other examples include
efforts directed toward the cytoskeletal protein FtsZ;110,111
the
sortase transpeptidases;112,113
the GlmU uridyltransferase
(from a lead identified by high-through put screening);114,115
and the Mur enzymes of peptidoglycan biosynthesis.116–118
The qualification of “promising” for all of these structures
(again) refers to the momentous difficulty of taking a struc-
ture from in vitro activity to clinical efficacy. But this is a dif-
ficulty that is universal for all of drug discovery. A chemist's
reflection on the ungainly heterocyclic structures that are
approved inhibitors against the kinases of human cancer119
leads to the conclusion that however momentous the diffi-
culty, the difficulty can be surmounted if the resources and
incentives are in place. Antibiotic discovery is challenging.
But it is not evident that its requirements for resources and
incentives are any greater than for any other target, or any
other disease. Rather, it is simply that neither the correct
resources nor the correct incentives are fully in place.
The conclusion that antibacterial drug discovery is a sur-
mountable challenge also stands on the ingenuity of Nature.
If the golden age of antibiotic discovery has passed, a new
era of natural product discovery is dawning.120–123
The antibi-
otics identified in the “golden age” of discovery originated
from extraordinary scientific perspicacity. While this require-
ment has not lessened with time—the challenge of finding
and then isolating (or replicating by total synthesis) a natural
product, on the mass scale required for antibiotic activity,
cannot be understated—the chemist today has an unprece-
dented ability not just to manipulate secondary biosynthesis,
but also to interrogate a vastly greater diversity of bacterial
and fungal species.124–137
Many of the genes for secondary
metabolism are under epigenetic control.138–140
One can now
pair the sequencing of a genome in order to identify the
genes dedicated to secondary metabolite biosynthesis, with
epigenetic activation of what often are silent biosynthetic
pathways. For example, application of this strategy to a fila-
mentous fungus, exploiting histone deacetylase inhibition to
alter gene expression, activated 75% of the genes involved in
secondary biosynthesis and resulted in the expression of ten
secondary metabolites, four of which were new.141
There is
no reason to believe that this strategy is not general. It is a
strategy that could diversify access to both exploratory anti-
bacterials, such as the nybomycin class of gyrase inhibitors142,143
as well as proven antibiotics such as the glycopeptides.144–149
Nor will it necessarily require a small molecule epigenetic modi-
fier: interspecies communication within the microbial “inter-
actome” has the same ability.150–153
Future natural product dis-
covery will not be limited to the particular proteins encoded by
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the genes of an organism.124
We now have such a grasp on the
modular organization of polyketide assembly that manipulation
of the modules is feasible.55,154–156
Future natural-product dis-
covery will not be limited to the genome of a single
organism,132,133,157–160
nor to the multimodular synthases they
may encode, as evidenced by the emerging ability to reprogram
the biosynthetic function of these synthases.161,162
A compelling
example of the future possibilities for the discovery of antibi-
otics that were previously hidden, is the use of microbial co-
culture to elicit antibiotic expression by the so-called “dark” or
“uncultivatable” bacteria.145,163–166
This strategy culminated in
the discovery of the Gram-positive active, cell-wall biosynthesis-
targeting depsipeptide, teixobactin.167
The transformation of a new structure from Nature into a
clinically useful antibiotic follows in many cases combined
empirical synthetic tailoring with property-based and
structure-based design.69,168,169
Recent exemplifications (from
among many) include structural development of the tetracy-
clines,69
the glycopeptides,170,171
and the antifolates.172–175
The selection of a clinical candidate among chemical struc-
tures with similar in vitro characteristics will be facilitated by
an emerging new pharmacological criterion, a long residence
time for drug engagement of its target.176–182
Structures that
possess this ability achieve an advantageous kinetic selectiv-
ity, wherein off-target interactions are minimized. The rele-
vance of this criterion was exemplified recently during the
assessment of inhibitors of LpxC, a key enzyme in the biosyn-
thetic pathway to the lipopolysaccharides of the outer mem-
brane of the Gram-negative bacteria. LpxC is a validated anti-
bacterial target. However, its conformational mobility as a
protein enables it to accommodate resistance muta-
tions.183,184
Incorporation of kinetic performance, measured
as the on-rate for formation and off-rate for breakdown
within a series of LpxC inhibitors, yielded a pharmacody-
namic model wherein the dose–response curves for these
inhibitors in a Pseudomonas aeruginosa animal model of
infection was predicted.185
The use of comparative kinetic
data in compound evaluation will facilitate the pre-clinical
assessment of exploratory antibacterial structures.
Endless antibiotics: a biological perspective
Notwithstanding the fact that antibiotic resistance in Nature
coincided with the discovery of the antibiotics, the conceptu-
alization of “resistance” continues to evolve.186–188
This evolu-
tion is multi-dimensional. Its directions include not just the
mechanismIJs) of the resistance against a particular anti-
bacterial, but the spectrum of thought ranging from reflection
on the ecological purpose of the antibiotics, to the criteria
necessary to attain the multi-agent synergy against infectious
disease that the future may demand. Here we offer a concise
perspective on the eclectic breadth of the conceptualization of
bacterial resistance, with emphasis on (and acknowledgement
of) the most recent contributions defining its directions.
The emerging methodologies to probe the relationships
among bacterial pathways and antibacterial structures will
prove transformative for antibacterial discovery.189,190
Both
the “Comprehensive Antibiotic Resistance Database”
(“CARD”: http://arpcard.mcmaster.ca)191,192
and the NCBI
National Database for Antimicrobial Resistant Organisms
(http://www.ncbi.nlm.nih.gov/projects/pathogens/) address the
bioinformatic aspects of these relationships. One example of a
new methodology to complement bioinformatics analysis is the
use of sub-μm fluorescence to attain resolution within the
dimensions of the bacterial cell. With this resolution, an imme-
diate visual assignment of the antibacterial mechanism by
examination of the cytological profile of fluorescent reporters as
a result of the presence of the antibacterial.193,194
A second
example is the use of imaging mass spectrometry to evaluate
specialized metabolite synthesis by Streptomyces coelicolor as
the result of interspecies interaction.150,151
This methodology
has the promise of improving our understanding of bacterial
communication, especially as it relates to antibiotic synthesis,
mechanism, and resistance responses. With respect to these
mechanistic aspects, it is prudent for us to appreciate how poor
is our understanding, even for the “golden age” antibiotics. The
venerable class of β-lactam antibiotics exemplifies our igno-
rance. We are reminded that there is an enormous breadth of
structure around the β-lactam core among the sub-families of
this class. Individual β-lactam structures show differential affin-
ity for their Penicillin-Binding Protein (PBP) enzyme targets.
Each bacterium has a family of PBPs, and each of these PBPs
uniquely contributes—some essentially, others much less so—
to the growth and shape of the bacterium. Hence, each
β-lactam structure uniquely profiles the PBP family of a bacte-
rium.195,196
This uniqueness explains why particular β-lactams
are clinically efficacious for infections by particular bacteria,
but does not reveal the mechanistic interconnection between
PBP inactivation and subsequent bactericidal cell lysis. While
recent profiling of the relationship among β-lactam structure,
PBP inactivation, and MIC value confirms the importance of
selective PBP inactivation, it also identifies particular β-lactams
for which the MIC does not coincide with PBP inactivation. The
answer to the “bactericidal mechanism of the β-lactams” is
remarkably incomplete.197–199
A further context around this incompleteness is our
equally rudimentary understanding of the ecological purpose
in Nature for the antibiotics. The conception that many natu-
ral products produced by microbes are messengers, a molecu-
lar realm termed by Davies as the “parvome”,200–204
is now
well accepted. But what is their message? The traditional
explanation for the antibiotics as defensive molecules to
secure and preserve an ecological niche is supported by
recent experiments.205,206
Nonetheless, the antibiotic concen-
trations used in chemotherapy vastly exceed the concentra-
tions attained in ecological niches, and accordingly we must
be mindful of understanding the bacterial responses to sub-
MIC (sub-lethal) antibiotic exposure.207,208
The proven rela-
tionships among quorum sensing,209–212
biofilm forma-
tion,213,214
and virulence establish communication as a key
role for the antibiotics of Nature.215–217
Antibiotics, even if
simplistically conceptualized as weaponry, communicate.
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Their communication ability is intimate to the complexity of
bacterial tolerance218
and persistence219–227
within the diver-
sity of the ecological microbiomes.5,228–231
Chemical commu-
nication among bacteria is understandably an evolutionary
force for genetic transformation19,208,232–234
and thus is one
and the same with resistance.
Here we return to the mysterious depth of the resistome,
and the underestimated ability of bacteria to adapt to what
we naively might believe to be an even more than decimating
assault by the antibacterial concentrations attained during
clinical use. We cannot be surprised that while we know that
antibiotics are powerful evolutionary forces, we do not under-
stand the relative pressure of these forces in particular eco-
logical niches235–237
and within the universe of resistance
mechanisms.238–241
Both new mechanisms for antibacterial
invention (such as the discovery that the allosteric regulation
of the essential PBP2a enzyme of methicillin-resistant Staphy-
lococcus aureus can be disrupted)109,242–244
and new mecha-
nisms to secure resistance (as just demonstrated for the tetra-
cyclines)245,246
will be found. We face the dilemma that while
the micobiome is heterogeneous247
and the natural state for
bacteria is a surface-bound community,248
there are compel-
ling arguments to study the behavior of individual bacte-
ria,249,250
even for the determination of the MIC for an
antibacterial.251
How is this labyrinth to be confronted for antibacterial
discovery? The obvious answer is the use of the antibiotics
themselves, as superlative chemical probes, to provide both
understanding and opportunity with respect to the conflu-
ence of targets and pathways. Two complementary themes
exemplify efforts toward such identification. One is the rela-
tionship of antibiotic activity to metabolism (defined in the
broadest sense). The second is the ability of antibacterial
pairs to synergize their respective antibiotic activities. A
direct relationship between metabolism and antibiotic activ-
ity is well recognized.252–257
Less understood is why the rela-
tionship directly correlates for some antibiotics, but indi-
rectly for others.258
The ability to correlate the mechanism of
ribosome-directed antibiotics, their antibiotic efficacy, and
the rate of growth of E. coli provides promise that an under-
standing of the key aspects of this relationship, in terms of
clinical strategies, will be forthcoming.259
A more demanding
question is for which bacteria, and for which circumstances,
the generation of reactive-oxygen species260
contributes253,261–265
or does not contribute266–268
to antibacterial efficacy. An answer
to this question may contribute (for example) to a mechanistic
understanding of how the new antibiotic lysocin acts through
interference with the menaquinone of the bacterial membrane;269
and whether the role of glutamate dehydrogenase activity in coor-
dinating FtsZ-dependent cell division in Caulobacter crescentus270
represents a potentially synergistic pathway confluence in bacteria
that have FtsZ-dependent bacterial division. Such synergism—col-
lateral sensitivity—is a central theme to the future discovery of
antibiotics.271–281
Exploration of this concept with respect to the
β-lactam antibiotics in S. aureus has identified synergistic conflu-
ence with inhibitors of its cell division pathway,282
of its
peptidoglycan biosynthesis pathway,283,284
and of its wall-
teichoic acid biosynthesis pathway.285–290
This latter correlation
is especially interesting, as the wall-teichoic acids are important
contributors to colonization.291,292
Collateral synergy is now also
demonstrated between the teichoic acids and the undecaprenyl
lipid biosynthesis pathway.205
The undecaprenyl lipids are attrac-
tive targets as bacteria have a small pool of these lipids to sup-
port cell-wall biosynthesis.293–296
Understanding just how to
achieve this sensitivity is incomplete,281,297,298
as evidenced by
other studies on the undecaprenyl pathway. Incomplete inhibi-
tion of undecaprenyl biosynthesis in B. subtilis induced a stress
response that resulted in increased resistance to other cell-wall-
active antibiotics.299
Lastly, even when the outcome for the
pairing of an antibiotic with a synergistic inhibitor is decisively
advantageous in pharmacological models, validating this out-
come in the clinic is especially challenging. Not only must safety
be proven for the pairing of the both entities, but for optimal
efficacy for the structures of the pair and dosing choices for the
pair, should correspond to matched pharmacokinetics of the two
entities. The current cluster of β-lactam/β-lactamase inhibitors in
clinical evaluation for Gram-negative bacterial infection reflects
not just their promise of efficacy as a pairing, but the ability to
bring to the clinical design the established clinical experience of
the β-lactam partner. The task is simpler when one of the entities
is known.
Conclusion
The title of this perspective pairs a declaration with a ques-
tion. The declaration is irrefutable. This perspective has
addressed the question, but without separation of the ques-
tion into its two very different contexts. New antibiotics will
be discovered. In this context of the question, our answer is
resoundingly positive. Indeed, the basis for this opinion is
the central theme of this perspective. There is, however, a
second context for this same question. Will these new antibi-
otics achieve clinical impact? The answer to this question is
less positive. The enthusiastic optimism and resoundingly
positive answer to the question in the first context, and
reserved (even deeply reserved) pessimism for the answer in
the second context, is not cognizant dissonance. At this time
good progress is being made with respect to the 10 × 20 ini-
tiative of the Infectious Diseases Society of America.300,301
New antibiotics (especially new β-lactamase-inhibitor
combinations)65,302–310
are reaching the clinic. Yet over this
same decade a fundamental transition has occurred with
respect to early antibiotic discovery. This task has trans-
itioned from major pharma companies to smaller biotechnol-
ogy companies, and to academic centers. An excellent exam-
ple of success from such collaboration is SMT-19969, now in
Phase II clinical trials for Clostridium difficile infection.311,312
SMT-19969 is a member of the synthetic, DNA-interacting
bis-benzimidazole class of structures. Its mechanism is not
gyrase inhibition, as is the case for other members of this
class.311
SMT-19969 shows good selectivity for C. difficile. As
it is less active against other Gram-positive anaerobes and
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the Gram-negative anerobes, and only weakly active against
both Gram-positive aerobes it has potential as a selective,
microbiome-sparing entity. Although the transition of early
discovery away from major pharma certainly does not itself
mean that antibacterial discovery and development will fal-
ter, there is reason for concern. The urgency for the preserva-
tion of existing antibacterials, and the discovery of new anti-
bacterials, is such that Nathan has argued for an open
discovery initiative embracing academic, industrial, founda-
tional, and governmental collaboration.313
Given the present
requirements for the size and scope of clinical evaluation
(although these requirements are changing for the better)
within the unchanging cost structure for the antibiotic mar-
ket, there are credible reasons for such a proposal. Absolute
ownership of intellectual property is a necessity for all new
drug entities. Acquisition of this ownership requires tight
integration of the timing of the patent prosecution with clini-
cal development. The financial return on the investment
required to bring an antibacterial to market, even using opti-
mistic estimates, is predicted to occur only in the final years
of the patent life. This sobering reality is illustrated (Fig. 1).
The necessity for a fundamental change in how the necessary
investment in the discovery and development of anti-infective
drugs is made appears inescapable.28,47,313,314
As we stated
emphatically a decade ago, bringing a new drug to market
(nor even the discovery of a new antibiotic) is not an instan-
taneous event.315
Achieving intellectual property ownership
while sustaining credible progression to the return on invest-
ment, in a development model where early discovery does
not tightly transition to clinical development, is a profound
challenge. The financial incentives for antibiotic discovery
must change if clinically relevant antibiotic discovery is to be
sustainable. The interim solutions of reconsidering old anti-
biotics316,317
or synergistic pairing of existing antibacterials
(as we have just discussed) are essential. But neither solution,
alone or together, offers the prospect of endless antibiotics.
Acknowledgements
Research in this laboratory is supported by a grant from the
National Institutes of Health (AI104987).
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